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Bendamustine hydrochloride in patients with refractory soft tissue sarcoma†
A noncomparative multicenter phase 2 study of the German sarcoma group (AIO-001)
Article first published online: 28 JUN 2007
Copyright © 2007 American Cancer Society
Volume 110, Issue 4, pages 861–866, 15 August 2007
How to Cite
Hartmann, J. T., Mayer, F., Schleicher, J., Horger, M., Huober, J., Meisinger, I., Pintoffl, J., Käfer, G., Kanz, L. and Grünwald, V. (2007), Bendamustine hydrochloride in patients with refractory soft tissue sarcoma. Cancer, 110: 861–866. doi: 10.1002/cncr.22846
Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2–6, 2006, Atlanta, Georgia.
- Issue published online: 2 AUG 2007
- Article first published online: 28 JUN 2007
- Manuscript Accepted: 29 MAR 2007
- Manuscript Revised: 21 MAR 2007
- Manuscript Received: 16 JAN 2007
- soft tissue sarcoma;
- alkylating agents;
- bendamustine hydrochloride;
For patients with advanced soft tissue sarcoma (STS), no standard treatment is established after previous chemotherapy with anthracyclines and ifosfamide. Bendamustine hydrochloride is a bifunctional alkylating agent that is not cross-resistant to other DNA-interacting substances including anthracyclines and oxazaphosphorines. It has shown single-agent activity in refractory lymphoma, myeloma, and some solid tumors. A phase 2 study was initiated to evaluate the efficacy of bendamustine in previously treated patients.
Thirty-six of 44 screened patients were included and received a total of 101 cycles (median, 2 cycles; range, 1–8 cycles), 21 as second-line treatment and 15 as third-line treatment. The median age was 55 years (range, 18–79 years). Bendamustine was given as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on 2 consecutive days and repeated every 28 days. Eighty-eight percent of cycles could be given without dose or schedule modification.
The toxicity profile was mild, consisting of National Cancer Institute Common Toxicity Criteria (CTC) grade 3 neutropenia in 11% and grade 3 anemia in 9% of patients. Nonhematologic toxicities were noticed with CTC grade 3 fever in 3% of patients. No other grade 3 toxicity and no treatment-related toxic deaths were observed. The best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 1 partial remission (3%) and disease stabilizations in 31% of patients. Six of 15 patients (40%) with leiomyosarcoma histology achieved stable disease. The estimated 3-month and 6-month progression-free survival rates were 35.3% and 23.5%, respectively, for all histologic subtypes included.
In patients with refractory STS, bendamustine is well tolerated and appears moderately effective, particularly in patients with leiomyosarcoma histology. Cancer 2007. © 2007 American Cancer Society.
Soft tissue sarcomas (STS) account for approximately 1% of all malignancies in adults. The histologic classification of STS is complex. More than 50 histologic subtypes can be discerned.1 From a clinical point of view, it is of utmost importance to detect tumors occurring in pediatric patients, who are particularly amenable to aggressive multimodality treatment in embryonal rhabdomyosarcomas or Ewing sarcoma. For patients with a sarcoma from the remaining heterogeneous group of STS of adult types, a cure can usually only be attained by radical resection.2 Approximately 25% of patients with newly diagnosed STS present with metastatic disease. Depending on the stage at presentation, an additional 25% to 50% of patients with locally advanced sarcomas will develop a recurrence. The median overall survival in patients with metastatic STS is approximately 12 months and the 5-year survival rate is approximately 5%. Once the disease has spread to distant sites, treatment is palliative in most cases. Among the “adult type” sarcomas, to date only a few subtypes of STS require a specific treatment (eg, imatinib in gastrointestinal stroma tumors).
Only a limited number of drugs have shown significant single-agent activity in adult STS patients: ifosfamide and the anthracyclines doxorubicin and epirubicin. The response rate for doxorubicin and ifosfamide has a positive dose-response curve, with single-agent response rates between 20% and 35% when doxorubicin is used at doses ≥75 mg/m2 and ifosfamide is used at doses ≥10 gm/m2.3–5 Although survival chances are generally limited in the entire cohort with metastatic disease, long-term survival may follow an optimal response to chemotherapy in a subgroup of patients.6
A number of additional substances has been tested for STS with only moderate success (eg, gemcitabine, dacarbacine, topotecan, and trofosfamide).7–11 No standard treatment option has been identified to date for patients with STS who fail previous treatment with anthracyclines and ifosfamide.
Bendamustine HCL is a bifunctional alkylating agent that is not cross-resistant to other DNA-interacting substances including anthracyclines and the oxazaphosphorines cyclophosphamide and ifosfamide. It has shown activity in refractory lymphoma, myeloma, breast cancer, and small cell lung cancer.12, 13 The toxicity profile is favorable, with the main toxicity being moderate suppression of bone marrow function. The good subjective tolerability renders the drug an interesting candidate for palliative treatment situations in a disease that is, in principle, responsive to alkylating agents. The present study was launched to test the activity of bendamustine HCL as a single agent in patients with previously treated STS.
MATERIALS AND METHODS
Objective, Endpoints, Study Design, and Statistics
The principal objective of the study was to evaluate the efficacy of bendamustine HCL in patients with metastatic STS who had progressed after or during an anthracycline-based chemotherapy. The primary endpoint was overall response rate (complete response [CR] + partial response [PR]) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST).14 Secondary endpoints were progression-free rate (PFR) and the safety profile of bendamustine HCL. Adverse drug reactions were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC; version. 2.0).
The study was designed as an open-label, multicenter, noncomparative phase 2 clinical trial. A 2-stage study design according to Simon et al. with an α error of 10% and a power of 90% (assumptions: P0 = 10%, P1 = 30%, 2-sided) was chosen.15 The sample size was 14 patients for the first stage. If at least 1 response was observed in the first stage, accrual was to be continued until 28 patients were evaluable for response. The protocol was approved by the ethical review board of Tuebingen University Medical Center and by the local review boards of all the participating centers.
Inclusion and Exclusion Criteria
Patients were required to have histologically proven, unresectable STS of any grade that had progressed during or recurred after chemotherapy with doxorubicin and/or ifosfamide. They needed to be at least 18 years of age, have measurable or evaluable disease according to RECIST criteria, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, a life expectancy of at least 3 months, and adequate function of bone marrow and kidneys (creatinine level <1.5 × the upper limit of normal [ULN], a white blood count >2500/μL, and a platelet count >75,000/μL). Informed consent was required from all patients.
Patients were excluded from the study for the following reasons: previous or concomitant radiation of the only indicator lesion, elevated liver functions tests (aspartate or alanine aminotransferase >3 ×ULN or, in the case of documented liver metastases, >5 × ULN), pathologic clotting tests (prothrombin time or the activated partial thromboplastin time >1.5 × ULN), uncontrolled infection, prior therapy with bendamustine HCL, second malignancy within the previous 5 years other than basal cell carcinoma of the skin, carcinoma in situ of the cervix or the bladder, congestive heart failure (New York Heart Association [NYHA] scale III or IV), symptomatic cerebrovascular insufficiency, central nervous system metastases, interval to prior chemotherapy of <4 weeks, and a lack of contraception in women of childbearing potential.
Treatment Schedule and Dose Modification
Bendamustine HCL was administered as a 30-minute infusion at a dosage of 100 mg/m2 body surface area on Days 1 and 2 every 28 days. Treatment interruption for 1 week was performed when granulocytopenia or thrombocytopenia of NCI CTC grade ≥2 were evident on Day 29. In case of grade 3 or 4 hematotoxicity, treatment was postponed for 7 days. In case of nonhematologic toxicity of CTC grade 2 or 3, treatment was delayed until symptoms resolved to grade 0 or 1 and the bendamustine HCL dose was reduced to 75% in the subsequent cycles. In the case of first recurrence of toxicity grade 2 or 3, a further reduction to 50% of the initial dose was allowed. The third occurrence of toxicity resulted in termination of the study. After the first occurrence of grade 4 nonhematologic toxicity, patients were either taken off study immediately or the treatment was delayed as described above and the dose reduced to 50% of the dose for the subsequent cycles at the discretion of the treating physician. Dose re-escalations were not allowed. Blood cell counts were performed weekly; X-ray, ultrasound, or computed tomography scans for evaluation of treatment response were performed at the end of every second cycle.
Between September 2002 and August 2006, 44 patients were screened and 36 patients were available for protocol inclusion. The median age of the study population was 55 years (range, 18–79 years); 20 patients were women and 16 were men. The most frequent histologic subtype was leiomyosarcoma (n = 15 patients), followed by pleomorphic sarcoma, not otherwise specified (NOS) (n = 11 patients). The remaining cases were dedifferentiated liposarcoma (n = 4 patients), synovial sarcoma (n = 2 patients), pleomorphic rhabdomyosarcoma (n = 1 patient), and fibrosarcoma (n = 1 patient), as well as 1 patient each with a malignant peripheral nerve sheath tumor and a refractory primitive neuroectodermal tumor. Tumor grading according to the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) was grade 1 in 2 patients and grade 2/3° in 29 patients. Grading was not applicable for 5 patients.
All patients were pretreated with 1 (n = 21 patients) or 2 (n = 15 patients) prior lines of chemotherapy. The first-line treatment consisted either of the combination of doxorubicin and ifosfamide (n = 23 patients), doxorubicin alone (n = 11 patients), or ifosfamide alone (n = 2 patients). The patients had received a median number of 6 cycles of chemotherapy in the prior course of the disease (range, 1–12 cycles). The majority of the patients (n = 20; 56%) developed disease progression during the previous chemotherapy, 10 patients (28%) had a recurrence within 6 months after the completion of pretreatment, and 6 patients (17%) had a progression-free interval of >6 months after the initial treatment (see Table 1 for details).
|No. of patients||%|
|Total no. included||36||100|
|Evaluable for response*||35||97|
|Evaluable for toxicity||35||97|
|ECOG performance status|
|Age (range), y||55 (18–79)|
|Grading according to FNCLCC|
|Sites of lesions|
|Prior regimen applied|
|Combination of both||23||64|
|Status prior to protocol inclusion|
|Progression during chemotherapy||20||56|
|Relapse <6 mo after chemotherapy||10||28|
|Relapse >6 mo after chemotherapy||6||17|
Treatment and Toxicity
A total of 101 cycles were given (median, 2 cycles; range, 1–8 cycles). Approximately 89% of the cycles were given without dose modification or delay. The encountered toxicities were mild to moderate. NCI CTC grade 3 toxicity consisted only of anemia and leukocytopenia in 3 and 4 patients, respectively. Nonhematologic toxicity consisted of grade 3 fever/infection and allergic reaction in a single patient each (3%) (see Table 2 for details).
|No. of patients||%||No. of patients||%|
|PNP, neurologic disorders||4||11||0||0|
|Shortness of breath||9||26||0||0|
At the first response assessment after 2 months, 1 patient (3%) attained a PR. Eleven patients (31%) demonstrated stable disease. Fourteen patients (39%) were found to have progressive disease at planned restaging and 9 patients (25%) patients showed clinically overt disease progression before application of the second cycle and were taken off the study. One patient did not receive assessment at that timepoint.
Twenty-four patients were taken off study due to progressive disease, 1 patient due to toxicity (immediate-type hypersensitivity reaction), and another due to a decreasing performance status. Two patients withdrew their consent and 1 patient was lost to follow-up. Six patients stopped treatment per protocol after completion of 6 cycles. One patient who was treated with bendamustine HCL developed acute myeloid leukemia M5 according to the French-American-British (FAB) classification 1 month after the initiation of treatment (cumulative dose of bendamustine HCL of 200 mg/m2). The patient had received prior treatment with doxorubicin and trofosfamide and had undergone palliative radiation treatment of the sacral bone. The short interval between the administration of study mediation and the onset of leukemia would be exceptional for a treatment-induced myeloid leukemia, even though a causal relation to the study medication cannot be definitely excluded.
In an intent-to treat setting the PFR rates at 3 and 6 months were 35.3% (95% confidence interval [95% CI], 19.3–51.3%) and 20.6% (95% CI, 7.1–34.1%), respectively. Among the largest group of histologic subtypes, the leiomyosarcomas, the PFR rates for these patients were 42.9% and 35.7% at 3 and 6 months, respectively (Fig. 1). Overall survival data with respect to leiomyosarcoma and nonleiomyosarcoma strata are shown in Figure 2.
Patients with metastatic STS have a dismal prognosis. Once treatment with doxorubicin and ifosfamide have failed, only a few established treatment options can be offered to these patients. Numerous agents have been investigated in exploratory phase 2 clinical trials. Among these, dacarbazine is most likely the most commonly used drug. However, the response duration has been disappointing. Similar results have been previously reported for gemcitabine.9, 16 Promising data were recently available for the combination of gemcitabine and docetaxel in leiomyosarcoma and in other types of adult STS.17, 18 This phase 2 study was designed to evaluate the promise of a second-line or third-line chemotherapy with bendamustine HCL.
In keeping with the data from trials using bendamustine HCL for patients with myeloma, lymphoma, and breast cancer, the drug was well tolerated. The major toxicities observed were leukocytopenia and thrombocytopenia. No serious infections were observed, nor did bleeding complications occur. The vast majority of the cycles could be given without dose reductions or delays. However, the majority of the patients received only 2 cycles before the treatment was withdrawn due to disease progression. Thus, the cumulative toxic effects could easily be missed in the study.
Only 1 patient achieved an objective remission (3%) in the study population. In addition, a total of 11 patients (31%) experienced disease stabilization at the first response assessment. These data are in keeping with results of drugs commonly used in second-line therapy in refractory sarcoma patients, such as ifosfamide or dacarbazine. Of note, a substantial quantity of 15 patients with leiomyosarcomas had disease stabilization at the time of initial evaluation, indicating that this entity is likely to respond to bendamustine HCL. If patients with nonleiomyosarcomas were to be excluded, the rate of disease stabilization rates—a clinically meaningful result with regard to the limited options available to help these patients—were 42.9% and 35.7% at 3 and 6 months, respectively.19 This appears promising in the context of recently reported results of new drug classes such as mTOR inhibitors, which failed to demonstrate superior activity in refractory STS subtypes.
In summary, bendamustine HCL demonstrated moderate activity in patients with STS, particularly of leiomyosarcoma histology. Given the favorable toxicity profile and the encouraging disease stabilization rate in leiomyosarcomas, it appears justified to further explore the drug in combination with established agents.
- 14New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92: 205–216., , , et al.
- 18A SARC multicenter phase III study of gemcitabine (G) vs. gemcitabine and docetaxel (G+D) in patients (pts) with metastatic soft tissue sarcomas (STS). J Clin Oncol. 2006; 24: 18S. Abstract 9514., , , et al.